CKD-Induced Oxidative Twitch Muscle Atrophy is Mediated by Transforming Growth Factor-β.

Background: Understanding the vicious cycle driving renal impairment progression and skeletal muscle atrophy in chronic kidney disease (CKD) is crucial. Therefore, this study aimed to examine the role of transforming growth factor-beta (TGF-β) in promoting skeletal muscle atrophy in CKD.

Methods: A combined model of 2/3 nephrectomy and unilateral ureteral ligation, as we previously reported, was used for CKD mice. Skeletal muscle weight and changes in skeletal muscle fiber twitch type were evaluated. Using C2C12 cells, a skeletal muscle myoblast cell line, molecules that induce a reduction in type IIa muscle fibers in CKD were identified. The identified molecule, TGF-β, was administered to mice to investigate its effects on muscle fiber-type changes. Furthermore, the effects of administering a TGF-β inhibitor to CKD mice were evaluated.

Results: In CKD mice, myosin heavy chain (MyHC)-specific antibody immunostaining showed an increase in atrophied MyHC IIa (oxidative twitch) muscle fibers. CKD mouse serum preferentially induces MyHC IIa fiber atrophy in C2C12 cells. TGF-β-treated mice had reduced levels of oxidative metabolic skeletal muscle and oxidative type IIa fiber, similar to CKD mice. Furthermore, TGF-β inhibitor treatment prevented the CKD-associated decrease in oxidative type IIa muscle fiber size and reduced exercise capacity.

Conclusions: These findings indicate that TGF-β causes skeletal muscle deterioration in CKD by reducing oxidative metabolism and inducing type IIa fiber atrophy. In addition, our results emphasize that reversing the disrupted MyHC phenotype in CKD is a potential therapeutic target for CKD-induced muscle atrophy.